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Publication Abstract from PubMed

Humans lack the capacity to produce the Galalpha1-3Galbeta1-4GlcNAc (alpha-gal) glycan, and produce anti-alpha-gal antibodies upon exposure to the carbohydrate on a diverse set of immunogens, including commensal gut bacteria, malaria parasites, cetuximab, and tick proteins. Here we use X-ray crystallographic analysis of antibodies from alpha-gal knockout mice and humans in complex with the glycan to reveal a common binding motif, centered on a germline-encoded tryptophan residue at Kabat position 33 (W33) of the complementarity-determining region of the variable heavy chain (CDRH1). Immunoglobulin sequencing of anti-alpha-gal B cells in healthy humans and tick-induced mammalian meat anaphylaxis patients revealed preferential use of heavy chain germline IGHV3-7, encoding W33, among an otherwise highly polyclonal antibody response. Antigen binding was critically dependent on the presence of the germline-encoded W33 residue for all of the analyzed antibodies; moreover, introduction of the W33 motif into naive IGHV3-23 antibody phage libraries enabled the rapid selection of alpha-gal binders. Our results outline structural and genetic factors that shape the human anti-alpha-galactosyl antibody response, and provide a framework for future therapeutics development.

Genetic and structural basis of the human anti-alpha-galactosyl antibody response.,Langley DB, Schofield P, Nevoltris D, Jackson J, Jackson KJL, Peters TJ, Burk M, Matthews JM, Basten A, Goodnow CC, van Nunen S, Reed JH, Christ D Proc Natl Acad Sci U S A. 2022 Jul 12;119(28):e2123212119. doi:, 10.1073/pnas.2123212119. Epub 2022 Jul 8. PMID:35867757^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.